Tissue-specific enhancers seem to play a major role in controlling developmentally regulated gene expression. Expression of rearranged immunoglobulin genes introduced into both lymphoid and non-lymphoid cells has led to the identification of tissue-specific transcriptional enhancer sequences in the major intron between the J and C region of the immunoglobulin gene. We have shown that immunoglobulin gene expression may also be controlled by tissue-specificity of the promoter. The K chain V region promoter contain sequences at the 5' side of the promoter which seems to inhibit promoter activity in non-lymphoid cells. Tissue-specificity of immunoglobulin gene enhancers could be due to its interaction with some, as yet unidentified, trans-acting regulatory factors that may be present only in lymphoid cells. We have constructed special plasmid vectors containing the coding sequences of a dominant selectable marker gene that confers resistance to neomycin. These coding sequences are driven by an immunoglobulin gene promoter and the various vectors contain different immunoglobulin gene enhancers. By introducing these hybrid genes, we hope to create recipient cells that can be used to directly bisolate genes that code for putative trans-acting regulatory factors. Isolation of these regulatory genes will greatly enhance our ability to understand the regulation of tissue-specific gene expression at the molecular level.